Laminins were identified in late 1970's as extracellular matrix proteins and components of basement membranes (Martin and Timpl, 1987) and they presently form a growing family of glycoproteins with diverse functions (Miner and Yurchenco, 2004). In recent years, the central nervous system functions of various laminins have been extensively studied, and their multiple roles in the developing and mature CNS have started to emerge (Liesi, 1990; Miners and Mercado, 2003). Numerous studies have established that laminins are widely expressed in both CNS neurons and glial cells (Wiksten et al., 2004b; Liesi et al., 2001a). One of the neurite outgrowth domains of laminin-1 has been mapped to the C-terminal decapeptide RDIAEIIKDI (Liesi et al., 1989) of the γ1-chain of laminin-1. Specifically, the γ1 laminin has been linked in promoting neurite outgrowth (Liesi et al., 2001b), neuronal migration (Liesi, 1990), and axon guidance (Wiksten et al., 2003).
Interestingly, the neurite outgrowth function of the γ1 laminin is mediated by a tri-peptide sequence KDI (Lys-Asp-Ile) located in C-terminus of the protein (Liesi et al. 2001b). This tri-peptide enhances both viability and directional neurite outgrowth of human spinal cord neurons in vitro (Wiksten et al., 2003; Liebkind et al., 2003). Recent data indicate that the KDI domain possesses dramatic neuroprotective functions in vivo: it was shown (1) to prevent kainic acid induced neuronal death in hippocampal and cortical areas of the rat (Wiksten et al., 2004b), and (2) to promote healing and functional regeneration of surgically induced spinal cord injury resulting in hind limb paralysis of adult rats (Wiksten et al., 2004a). Microscopic and molecular analyses of KDI-treated spinal cords and hippocampal tissues indicate that application of soluble KDI-peptide reduces tissue damage at the lesion site and enables both neurite outgrowth through the injured area and neuronal survival (Wiksten et al., 2004a and 2004b).
Previous studies have also shown aggregation of inwardly rectifying potassium channels (Guadagno and Moukhles, 2004) and most recently voltage gated calcium channels (Nishimune et al., 2004) by binding of a particular laminin to the channel protein, but no electrical responses were reported for this interaction.
Even though the adhesive properties have been shown to play an important role in such biological events as promotion of neurite outgrowth, neuronal migration and regeneration, the data of the present invention indicate that the neurite outgrowth KDI domain of γ1 laminin has additional diverse and important functions that shed new relevance for expression of γ1 laminin in adult CNS neurons (Wiksten et al., 2004b), and in CNS after trauma (Liesi and Kauppila, 2002) or in a neurological disorder, such as Alzheimer's disease (Murtomäki et al., 1992; Palu and Liesi, 2002).
As compelling evidence indicates that glutamate neurotoxicity (glutamate-mediated neuronal death, excitotoxicity) is a major player in all CNS trauma and neurodegenerative disorders (Mattson, 2003), most of the presently available novel drugs used clinically to treat patients with Alzheimer's disease and ALS or stroke are inhibitors of glutamate receptor function. However, many of these drugs cause significant side effects, e.g. neurotoxicity. Therefore, novel, effective, safe and non-toxic inhibitors of this receptor function are constantly needed.